title: Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations.
abstract: Ovarian cancer is a highly lethal gynecological cancer, and its causes remain to be understood. Using a recently identified tumor suppressor gene, GT198 (PSMC3IP), as a unique marker, we searched for the identity of GT198 mutant cells in ovarian cancer. GT198 has germ line mutations in familial and early onset breast and ovarian cancers and recurrent somatic mutations in sporadic fallopian tube cancers. GT198 protein has been shown as a steroid hormone receptor coregulator and also as a crucial factor in DNA repair. In this study, using GT198 as a marker for microdissection, we find that ovarian tumor stromal cells harboring GT198 mutations are present in various types of ovarian cancer including high and low grade serous, endometrioid, mucinous, clear cell, and granulosa cell carcinomas and in precursor lesions such as inclusion cysts. The mutant stromal cells consist of a luteinized theca cell lineage at various differentiation stages including CD133(+), CD44(+), and CD34(+) cells, although the vast majority of them are differentiated overexpressing steroidogenic enzyme CYP17, a theca cell-specific marker. In addition, wild type GT198 suppresses whereas mutant GT198 protein stimulates CYP17 expression. The chromatin-bound GT198 on the human CYP17 promoter is decreased by overexpressing mutant GT198 protein, implicating the loss of wild type suppression in mutant cells. Together, our results suggest that GT198 mutant luteinized theca cells overexpressing CYP17 are common in ovarian cancer stroma. Because first hit cancer gene mutations would specifically mark cancer-inducing cells, the identification of mutant luteinized theca cells may add crucial evidence in understanding the cause of human ovarian cancer.
authors.affiliation: From the Cancer Center and.
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Lahcen
authors.initials: L
authors.lastname: Jaafar
authors.forename: John I
authors.initials: JI
authors.lastname: Risinger
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Nahid F
authors.initials: NF
authors.lastname: Mivechi
authors.forename: Lan
authors.initials: L
authors.lastname: Ko
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013254:Steroid 17-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013799:Theca Cells / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D009687:Nuclear Proteins; C443678:PSMC3IP protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D013254:Steroid 17-alpha-Hydroxylase
keywords: Ovarian Cancer; Ovary; Steroid Hormone; Stromal Cell; Theca Cell; Tumor Microenvironment; Tumor Suppressor Gene